The field of the invention is electrical property measurement and imaging systems, and methods related thereto. More particularly, the invention relates to characterizing a tissue as cancerous or non-cancerous using the measured electrical characteristics of the tissue.
Screening mammography has been the gold standard for breast cancer detection for over 30 years, and is the only available screening method proven to reduce breast cancer mortality. However, the sensitivity of screening mammography varies considerably. The most important factor in the failure of mammography to detect breast cancer is radiographic breast density. In studies examining the sensitivity of mammography as a function of breast density, the sensitivity of mammography falls from 87-97 percent in women with fatty breasts to 48-63 percent in women with extremely dense breasts. Additional drawbacks of conventional mammographic screening include patient discomfort associated with the compression of the breast. Diagnostic alternatives to mammography include ultrasound and MRI. The effectiveness of whole-breast ultrasound as a screening technique, however, does not appear to be significantly different from mammography. Furthermore, while MRI has an apparent increased sensitivity for the detection of breast cancer and is not affected by breast density, the high cost of bilateral breast MRI (approximately 20 times more expensive than mammography) has precluded its widespread use as a screening technique.
A high percentage of breast cancers are not detected at the screening stage. Studies show that 20-50% of breast cancers go undetected at the screening stage. In fact, it is estimated that by the time a tumor is detected by mammography it has been already been growing for upwards of 5-8 years. The motivation for early detection is great: when an invasive breast cancer is discovered at a small size, it is less likely to have metastasized and more likely correspond to a higher survival rate. For example, breast cancer detected in the early stage has a 5 year survival rate of approximately 96%, while the 5 year survival rate for late stage breast cancer falls to 20%.
After a suspicious lesion is found, medical professionals often rely on expensive biopsies to determine cancerous tissues. These procedures are neither fast nor patient-friendly. Surgical biopsy is recommended for suspicious lesions with a high chance of malignancy but fine-needle aspiration cytology (FNAC) and core biopsy can be inexpensive and effective alternatives. Both FNAC and core biopsy have helped to reduce the number of surgical biopsies, sparring patients anxiety and reducing the cost of the procedure. However, core biopsies have often failed to show invasive carcinoma and both FNAC and core biopsies can result in the displacement of malignant cells away from the target, resulting in misdiagnosis. Additionally, core biopsies have a limited sampling accuracy because only a few small pieces of tissue are extracted from random locations in the suspicious mass. In some cases, sampling of the suspicious mass may be missed altogether. Consequences include a false-negative rate of 1-7% (when verified with follow up mammography) and repeat biopsies (percutaneous or surgical) in 9-18% of patients (due to discordance between histological findings and mammography). The sampling accuracy of core needle biopsy is, furthermore, highly dependent on operator skills and on the equipment used.
Transforming growth factor beta (TGF-β) has long been known to have a role in the proliferation and cellular differentiation of many cell types, including breast tissue. Decreases in the TGF-β co-receptor TGF βRIII have recently been shown to correlate with the likelihood that a breast tissue will develop into malignant cancer. Moreover, the loss of TGF βRIII expression occurs early in the progression of cells from normal to cancerous, and is present in non-invasive stages of breast cancer such as ductal carcinoma in situ (DCIS). Therefore, determining the levels of TGF βRIII appears to be able to serve as an early indicator for breast tissue that is prone to develop into malignant cancer. Such a determination, however, would necessarily be done ex vivo on a biopsied tissue sample.
The characterization of cancerous tissue is divided into two groups: in situ and infiltrating lesions. In situ lesions are tumors that remain confined in epithelial tissue from which they originated. The tumor does not cross the basal membrane, thus the tumor and the healthy tissue are of the same nature (epithelial). The electrical impedance of an in situ lesion is thus dependent on the abundance of the malignant cells that will impact the macroscopic conductivity (which is influenced by the increase in sodium and water) and permittivity (which is influenced by the difference in cell membrane electrochemistry).
By contrast, infiltrating lesions are tumors that pass through the basal membrane. The malignant tissue has a different nature than normal tissue (epithelial vs. adipose). Epithelial tissue is compact and dense. Adipose tissue is composed of large cells that are mostly triglycerides. These structural differences have several impacts. First the normal tissue has a lower cellular density. Second, cell liquid of normal tissue is not as abundant as epithelial cells. Generally the radii of epithelial cells are less than adipose cells, indicating that the radius of cancerous cells is less than for normal cells. The impact on the fractional volume of cancerous cells versus normal cells is that the fractional volume of cancerous cells is greater than for normal cells. The reason for this is that the epithelial population is higher than for normal, adipose cells. Finally, the intracellular conductivity of cancerous cells is greater than for intracellular conductivity of normal cells. Moreover, the extracellular conductivity is higher because of the abundance of extracellular fluid (because of larger gaps between normal and cancerous cells). Thus, the conductivity of the infiltrated tissue will be greater than for normal tissue.
Electrical impedance tomography (EIT) is a process that maps the impedance distribution within an object. This map is typically created from the application of current and the measurement of potential differences along the boundary of that object. There are three categories of EIT systems: current injection devices, applied potential devices, and induction devices. Henderson and Webster first introduced a device known as the impedance camera that produced a general map of impedance distribution. The Sheffield System and its incarnations were the first generation EIT system. In the late 1980's, Li and Kruger report on an induced current device. In such a system, a combination of coils is placed around the object under test. A changing current in the coils produces a varying magnetic field that in turn induces a current in the object under test. As with the other drive method, electrodes are placed on the boundary of the object to measure the potential drops along the boundary.
Such electrical property imaging techniques are often referred to as “impedance tomography.” Most conventional electrical property imaging techniques are based on the premises that: 1) electrodes, or sensors, should be attached directly to the sample to be measured (for medical applications, the sample is a human body), and 2) current is injected sequentially through each electrode into the sample and the subsequent voltages measured. Therefore, these conventional EIT imaging techniques implement a “constant current/measured voltage” scheme.
In a departure from such conventional electrical property imaging techniques, U.S. Pat. No. 4,493,039 disclosed a method in which sensors are arranged in an array outside the object to be measured and during imaging of a sample, AC voltages are applied at a fixed amplitude while the current is measured. This approach, which is sometimes referred to as electrical property enhanced tomography (EPET), was further improved upon as described in U.S. Pat. No. 6,522,910 by filling the space between the object and the sensor array with an impedance matching medium.